Erythropoiesis in clinical practice

Erythropoiesis is disturbed to a greater or lesser extent in almost all multisystem diseases and so the reader is referred to other chapters and references for specific examples. The aim of this chapter is to provide a framework for thinking about the process of erythropoiesis in clinical practice. The first stage involves the production of committed erythroid progenitors. The second involves controlling red cell production, which is mainly achieved via the oxygen sensor influencing the level of Epo, which, in turn, controls the numbers of late BFU-Es and CFU-Es, although many other hormones cytokines and growth factors may modify the response. The third phase requires terminal erythroid differentiation to mature red cells containing large amounts of specific proteins such as haemoglobin. This phase makes significant demands on a variety of nutritional factors and cofactors, particularly iron, vitamin B12 and folate, but also manganese, cobalt, vitamin C, vitamin E, vitamin B6

(pyridoxine), thiamine, riboflavin, pantothenic acid and amino acids. Absolute or relative deficiencies of these cofactors can negatively regulate erythropoiesis. The output from this process (red cell mass) is required to meet the demands for adequate tissue oxygenation, which, itself, has a major influence on the production of erythropoietin, thus completing the regulatory loop (Figure 2.9).

Simple diagnostic tools are available to test the circuit in a logical manner (also see Chapter 6). First, one can evaluate the overall level of erythropoiesis by estimating the ratio of myeloid precursors-erythroid precursors in the marrow (normally ~4:1, but with a very broad normal range). Total erythropoiesis can be measured accurately using radioactive (59Fe) ferrokinetic assays. The plasma iron turnover measures the total (i.e. effective and ineffective) amount of erythropoiesis, whereas the red cell iron utilization assay measures effective erythropoiesis. To a large extent, these two parameters can now be assessed much more easily by measuring the levels of soluble transferrin receptor (sTfR) and the reticulocyte count. Soluble sTfR is a truncated form of the receptor which circulates in a complex with trans-ferrin. The erythroblasts rather than the reticulocytes are the main source of sTfR and, when iron stores are adequate and available, measuring the level of sTfR (NR 5.0 ± 1.0 mg/mL) is a good guide to the total level of erythropoiesis. STfR levels are increased when erythropoiesis is stimulated and decreased when diminished. The interpretation of sTFR levels is complicated in iron deficiency as this condition independently raises the level of sTfR. The reticulocyte count (0.5-2.0% or 25-75 X 109/L) is raised in proportion to the degree of anaemia when erythro-poiesis is effective (e.g. uncomplicated response to bleeding), but is relatively low when erythropoiesis is ineffective (e.g. P-thalassaemia) or an abnormality prevents a normal response (e.g. nutritional deficiency).

The output of the system, the red cell mass, can be accurately measured by radioactive dilution techniques using 51Cr, but can often be reliably estimated from the haematocrit or concentration of haemoglobin. Changes in red cell size, shape and haemoglobin content, often reflected in the red cell morphology, may provide important guides to specific abnormalities in red cell maturation (e.g. haemoglobinopathies, thalassaemia,

Figure 2.9 Summary of the regulation of erythropoiesis with the key points for assessment boxed in blue. ME denotes assessment of the M/E ratio in the bone marrow.

nutritional deficiencies). If the red cell mass is appropriate to meet the demands for oxygenation then Epo production will be suppressed and the serum level will be in the normal range of (~25-50 mU/mL in cord blood and ~10-30 mU/mL in adults). If there is inadequate oxygenation, the level of Epo will, in general, be raised in proportion to the degree of anaemia (e.g. up to 3-10 U/mL after severe blood loss) unless there is some impediment to Epo production (e.g. chronic renal failure, anaemia of chronic diseases). For any given degree of anaemia the level of Epo in the blood may vary depending on the underlying conditions. For example, the levels tend to be very high in aplastic anaemia and less than anticipated in thalassaemia. This may reflect the different numbers of precursors in the marrow that are able to bind available Epo molecules, thus altering the number of free Epo molecules that are measured.

These apparently straightforward assessments may be more difficult to interpret when there are multiple causes of abnormal erythropoiesis, and in particular when complicated by nutritional deficiencies, which should always be evaluated in parallel with these studies. In addition to the common nutritional anaemias, the vast number of specific diagnostic tests to determine the inherited or acquired disorders that may perturb each phase of erythropoiesis are described elsewhere in this book.

Proper oxygen delivery to the tissues requires sufficient circulating mature red cells, and any appropriate therapy should be aimed at correcting this. An important caveat is that excessive red cells may cause a sluggish circulation that can cause ischaemia, leading to serious complications (e.g. myocardial infarction and stroke). The simplified circuit presented here to describe the process of erythropoiesis (Figure 2.9) indicates three potential routes for therapeutic intervention. The first is to correct nutritional deficiencies, usually iron and less commonly folate or vitamin B12. The recent discovery of the role of the iron-regulatory peptide hepcidin in the anaemias of chronic disorders suggests that some remaining common forms of anaemia related to this class (caused by inability to use stored iron) may be amenable to rational treatment in the not too distant future. A second frequently used approach is to correct anaemia, of any cause, with red cell transfusion, and the criteria for such treatment are set out in other sections of this book. The final approach is to increase erythropoiesis by administering recombinant human erythropoietin (rHuEpo). Following its considerable benefit to patients with the anaemia of chronic renal failure who are not capable of making normal levels of Epo, rHuEpo has been assessed in a wide range of disorders (e.g. aplastic anaemia, red cell aplasia, thalassaemia intermedia, cancer of all types, haematological malignancy, myelodysplastic syndrome, rheumatoid arthritis, autologous blood donors, after stem cell transplantation and more). A review of its effectiveness in these situations is beyond the scope of this chapter, but the considerable expense involved in treating patients, often over relatively long periods of time, with a hormone that does not always directly address the known pathophysiology of the anaemia requires careful consideration.

Finally, there are some conditions in which hormonal deficiency is known to contribute to anaemia (e.g. hypothyroidism, Addison's disease). In these cases appropriate correction of the hormonal deficiency logically helps correct the anaemia. Some rare forms of anaemia respond to a variety of therapies for unexplained reasons. For example, some cases of Diamond-Blackfan anaemia (DBA) respond to corticosteroids, and some cases of congenital dyserythropoietic anaemia (CDA) respond to ainterferon, suggesting that there are still many unknown aspects to this clinically important and intellectually fascinating process of erythropoiesis.

Erythropoiesis in the context of general haemopoiesis

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Dzierzak E (2003) Ontogenic emergence of definitive hematopoietic stem cells. Current Opinions in Hematology 10:229-34.

Joshi C, Enver T (2003) Molecular complexities of stem cells. Current Opinions in Hematology 10:220-8.

Marshall CJ, Thrasher AJ (2001) The embryonic origins of human haemopoiesis. British Journal of Haematology 112: 838-50.

Orkin SH (2000) Diversification of haemopoietic stem cells to specific lineages. Nature Review of Genetics 1: 57-64.

Tavian M, Hallais M-F, Péault B (1999) Emergence of intraembry-onic hematopoietic precursors in the pre-liver human embryo. Development 126: 793-803.

Wickramasinghe SN (1975) Erythropoiesis. In: Human Bone Marrow (SN Wickramasinghe, ed.), pp. 162-232. Blackwell Scientific Publications, Oxford.

Regulation and differentiation of erythroid cells

Beguin Y (2003) Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clinica Chimica Acta 329: 9-22.

Constantinescu SN, Ghaffari S, Lodish HF (1999) The erythropoietin receptor: structure, activation and intracellular signal transduction. Trends in Endocrinology and Metabolism 10:18-23.

De Maria R, Zeuner A, Eramo A et al. (1999) Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401:489-93.

Panzenbock B, Bartunek P, Mapara MY etal. (1998) Growth and differentiation of human stem cell factor/erythropoietin-depend-ent erythroid progenitor cells in vitro. Blood 92: 3658-68.

Safran M, Kaelin WG Jr. (2003) HIF hydroxylation and the mammalian oxygen-sensing pathway. Journal of Clinical Investigation 111: 779-83.

Transcription factors controlling erythropoiesis

Bungert J, Engel JD (1996) The role of transcription factors in erythroid development. Annals of Medicine 28: 47-55.

Cantor AB, Orkin SH (2002) Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21: 3368-76.

Gubin AN, Njoroge JM, Bouffard GG et al. (1999) Gene expression in proliferating human erythroid cells. Genomics 59:168-77.

Shivdasani RA, Orkin SH (1996) The transcriptional control of hematopoiesis. Blood 87:4025-39.

Sieweke MH, Graf T (1998) A transcriptional factor party during blood cell differentiation. Current Opinions in Genetic Develop-ment8: 545-51.

Erythropoiesis in clinical practice

Beguin Y (2003) Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clinica Chimica Acta 329: 9-22.

Eschbach JW (2000) Current concepts of anaemia management in chronic renal failure: impact of NKF-DOQI. Seminars in Nephrology 20: 320-9.

Muirhead N, Bargman JA, Burgess E etal. (1995) Evidence-based recommendations for the clinical use of recombinant human erythropoietin. American Journal of Kidney Disease 26: S1-24.

Samol J, Littlewood TJ (2003) The efficacy of rHuEPO in cancer-related anaemia. British Journal of Haematology 121: 3-11.

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